Degirmencay, Abdullah;
Thomas, Sharyn;
Mohammed, Fiyaz;
Willcox, Benjamin E;
Stauss, Hans J;
(2023)
Modifications outside CDR1, 2 and 3 of the TCR variable β domain increase TCR expression and antigen-specific function.
Frontiers in Immunology
, 14
, Article 1148890. 10.3389/fimmu.2023.1148890.
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Abstract
T cell receptor (TCR) gene modified T cells are a promising form of adoptive cellular therapy against human malignancies and viral infections. Since the first human clinical trial was carried out in 2006, several strategies have been developed to improve the efficacy and safety of TCR engineered T cells by enhancing the surface expression of the introduced therapeutic TCRs whilst reducing the mis-pairing with endogenous TCR chains. In this study, we explored how modifications of framework residues in the TCR variable domains affect TCR expression and function. We used bioinformatic and protein structural analyses to identify candidate amino acid residues in the framework of the variable β domain predicted to drive high TCR surface expression. Changes of these residues in poorly expressed TCRs resulted in improved surface expression and boosted target cell specific killing by engineered T cells expressing the modified TCRs. Overall, these results indicate that small changes in the framework of the TCR variable domains can result in improved expression and functionality, while at the same time reducing the risk of toxicity associated with TCR mis-pairing.
| Type: | Article |
|---|---|
| Title: | Modifications outside CDR1, 2 and 3 of the TCR variable β domain increase TCR expression and antigen-specific function |
| Location: | Switzerland |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.3389/fimmu.2023.1148890 |
| Publisher version: | https://doi.org/10.3389/fimmu.2023.1148890 |
| Language: | English |
| Additional information: | © 2023 Degirmencay, Thomas, Mohammed, Willcox and Stauss. This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/). |
| Keywords: | T cell function, TCR (T cell receptor), TCR-T therapy, TCRV, framework engineering, Humans, Receptors, Antigen, T-Cell, alpha-beta, T-Lymphocytes, Receptors, Antigen, T-Cell, Genes, T-Cell Receptor, Antigens |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10169308 |
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